【作者】 鲍诚； 柴静静； 李斌； 施兴华； 李媛；

【Author】 Cheng Bao;Jingjing Chai;Bin Li;Xinghua Shi;Yuan Li;Beijing Advanced Innovation Center for Food Nutrition and Human Health, Key Laboratory of Functional Dairy, College of Food Science and Nutritional Engineering, China Agricultural University;

【机构】 北京市食品营养与人类健康高精尖创新中心中国农业大学食品科学与营养工程学院；

【摘要】 肠道表面的粘液层是一种凝胶型的天然屏障,它限制了药物递送载体的有效扩散和吸收。文献报道纳米载体的形状可能会影响颗粒的粘液穿透能力。我们制备了四种具有不同粒径和形状的乳清蛋白纳米颗粒,分别是小球NS(30 nm),大球BNS(300 nm),长管LNT(20×800nm)和短管SNT(20×200 nm)及交联短管CSNT。利用Transwell小室扩散法和多重粒子示踪技术MPT法两种方法证明了粒径和形状对纳米颗粒穿透肠粘液层有影响,几种纳米颗粒在肠粘液中的扩散速率顺序为:BNS <LNT<CSNT <NS <SNT。同时扩散速率更快的纳米颗粒SNT在肠粘液层中具有最广的运动轨迹和最快的扩散系数,可见粒径较小的管状纳米颗粒具有潜在的穿透肠粘液层的能力。构建了Caco-2/E12细胞共培养模型,SNT具有最强的粘液细胞渗透能力,同时SNT表现出最佳的细胞摄取和跨膜转运能力。将几种纳米载体应用于姜黄素的包埋,最后证明SNT/Cur具有最高的生物利用率。最终建立了粗粒化分子模型来解释上述机理,发现短管具有在粘液网络孔径里飞移和抖动的能力,使其可以平行并且垂直运动,增强了其粘液渗透能力。以上结果表明,短管状的纳米载体将作为一种极具潜力的口服给药载体。更多还原

【Abstract】 Mucus is a viscoelastic biological hydrogel that adheres to the epithelial surface and is difficult to be penetrated by most nanoparticles, which limits the efficient oral drug delivery. In this study, we prepared five peptosomes(PSs) with various sizes, shapes and rigidities based on self-assembly of amphiphilic α-lactalbumin(α-lac) peptides from partial enzymolysis and cross-linking. Curcumin(Cur) was encapsulated in these PSs as a model hydrophobic compound. The mucus permeation of α-lac PSs and release of Cur were evaluated. Our results showed that short nanotube(SNT) exhibits excellent permeability in mucus, which enables the SNT arriving at epithelial cells quickly. Besides, SNT exhibits the highest cellular uptake and transmembrane permeability on Caco-2/HT29-MTX(E12) 3 D model. In vivo pharmacokinetic evaluation revealed that the SNT shows a highest curcumin bioavailability, which is 2.87-, 5.28-, 1.29-, 3.17-and 6.85-folds higher than that of long nanotube(LNT), big nanosphere(BNS), small nanosphere(SNS), crosslinked short nanotube(CSNT) and free Cur respectively. In the end, the mechanism of the high permeability of SNT through mucus was explained by coarse-grained molecular dynamics simulations, which indicated that the short timescale flying across pores of mucus network plays a key role. These findings revealed the tubular α-lac PSs could be a promising oral drug delivery system targeted to mucosal for improving absorption and bioavailability of hydrophobic drugs.更多还原